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NCT Number: NCT03466775

Anti-Angiotensin II Type 1 Receptor Antibodies and Kidney Transplant Outcomes

Incompatibility between non-genetically identical donors and recipients has been increasingly recognized as the main contributing factor to solid allograft rejection and failure, through the triggering of donor-specific responses mediated by T- and B-lymphocytes. The Human Leucocyte Antigen (HLA) system has been identified as the main target of donor-specific responses, especially through the production by the recipient of antibodies directed toward non-self donor HLA molecules expressed on the allograft endothelium. As a consequence, in organ transplantation, the current approach to immunological risk stratification, patient monitoring and rejection diagnosis is based on biomarkers derived from the HLA system. However, this approach does not provide a sufficient accuracy for the risk stratification and the diagnosis of immunological complications in solid organ transplantation, which still remain the dominant cause of allograft failure.

A recent body of evidence supports that specific non-HLA antigens expressed on the allograft endothelium may be relevant to allograft rejection, suggesting that a new strategy to transplant diagnostic testing at a non-HLA level would help to overcome the limitations of the current HLA-based approach to immunological assessment of transplant recipients. Among antibodies to non-HLA endothelial antigens, angiotensin II type 1 receptor activating antibodies have been the most widely reported antibodies to associate with the occurrence of allograft rejection, dysfunction and loss, even if their independent role, with respect to the presence of concomitant anti-HLA antibodies, has not been demonstrated.

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Key information

Conditions

Kidney Transplant Failure and Rejection Behavior Rejection, Psychology Social Behavior

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France, Paris, France

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About this study

The aims of this study are:

  • To assess the incidence of post-transplant anti-angiotensin II type 1 receptor antibodies within the first year after transplantation in an unselected population of kidney transplant recipients.
  • To investigate the incidence of biopsy-proven kidney allograft rejection according to the presence of post-transplant anti-angiotensin II type 1 receptor antibodies and of post-transplant concomitant donor-specific anti-HLA antibodies within the first year after transplantation, and to evaluate the incidence of rejection cases associated with anti-angiotensin II type 1-receptor antibodies that are not recognized by the current diagnostic approach based on HLA testing.
  • To investigate the allograft injury phenotype associated with post-transplant anti-angiotensin II type 1 receptor, using histopathology, immunochemistry and measurement of endothelial-associated transcript (ENDAT) expression level in allograft.
  • To evaluate the impact of post-transplant anti-angiotensin II type 1 receptor antibodies on kidney allograft survival up to 7 years after inclusion, in univariate and multivariable survival models including clinical, histological and immunological risk factors for allograft loss.

This study includes kidney recipients transplanted between January 1, 2008 and December 31, 2012 at Necker and Saint-Louis Hospitals (Paris, France), who undergo screening for post-transplant anti-angiotensin II type 1 receptor antibodies and simultaneous kidney allograft biopsy within the first year after transplantation, either at the time of an episode of rejection in the first year after transplantation or at 1 year after transplantation in the absence of previous rejection episode.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Kidney recipient transplanted between January 1, 2008 and December 31, 2012
  • Kidney recipient over 18 years of age
  • Simultaneous histological and serological assessment within the first year after transplantation, including i) kidney allograft biopsy, ii) assessment of donor-specific anti-HLA antibodies, and available stored serum for anti-angiotensin II type 1 receptor antibody assessment

Exclusion criteria

  • No simultaneous histological and serological assessment within the first year after transplantation, including i) absence of serum available for anti-angiotensin II type 1 receptor antibody assessment, and/or ii) absence of donor-specific anti-HLA antibody testing, and/or iii) absence of kidney allograft biopsy
  • Inadequate kidney allograft biopsy according to the Banff classification for allograft rejection
  • Combined transplantation

Treatment and study plan

Anti-angiotensin II type 1 receptor antibody measurement

Diagnostic Test

Anti-angiotensin II type 1 receptor antibodies are assessed using quantitative ELISA in stored serum samples obtained within the first year after transplantation

Measurement of ENDAT expression level allograft

Diagnostic Test

Endothelial-associated transcript expression level is assessed using microarray in stored kidney allograft biopsies obtained within the first year after transplantation

Allograft survival

Other

Allograft rejection appearance

Other

Primary outcomes

  1. Incidence of biopsy-proven kidney allograft rejection according to the presence of post-transplant circulating anti-angiotensin II type 1 receptor antibodies within the first year after transplantation

    Time frame: One year after transplantation

    Anti-angiotensin II type 1 receptor antibody positivity is defined by serum concentration >10 U/mL using quantitative ELISA. Stratified analysis is performed according to the presence of post-transplant concomitant circulating donor-specific anti-HLA antibodies detected by single antigen bead assay in serum. Allograft rejection is defined on the basis of the 2015 update of the Banff classification for allograft rejection.

  2. Comparison of allograft injury phenotype according to post-transplant anti-angiotensin II type 1 receptor antibody status and concomitant donor-specific anti-HLA antibody status

    Time frame: One year after transplantation

    Injury phenotype is based on histological allograft elementary lesions defined by the Banff classification (glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, endarteritis, chronic allograft glomerulopathy, interstitial fibrosis, tubular atrophy, arteriosclerosis, arteriolar hyalinosis, C4d deposition in peritubular capillaries).

  3. Association between the presence of post-transplant circulating anti-angiotensin II type 1 receptor antibodies and time to kidney allograft

    Time frame: Up to seven years after inclusion

    Univariate and multivariable models are performed, including adjustment for recipient age and gender, biopsy indication, glomerular filtration rate, proteinuria, presence of post-transplant circulating donor-specific anti-HLA antibodies and histological elementary lesions defined by the Banff classification, assessed at the time of antibody detection.

Secondary outcomes

  1. Incidence of anti-angiotensin II Type 1 receptor antibodies in kidney transplant recipients within the first year after transplantation

    Time frame: One year after transplantation

    Anti-angiotensin II type 1 receptor antibody positivity is defined by serum concentration >10 U/mL using quantitative ELISA.

  2. Comparison of endothelial-associated transcript expression (ENDAT) levels according to anti-angiotensin II type 1 receptor antibody status and donor-specific anti-HLA antibody status

    Time frame: One year after transplantation

    ENDAT expression levels are measured in kidney allograft biopsies performed at the time of antibody detection, showing microcirculation inflammation (sum of glomerulitis and peritubular capillaritis Banff scores >1), using microarray technology.

Sponsors and collaborators

Lead sponsor

Paris Translational Research Center for Organ Transplantation

Other

Collaborators

  • Center for Cardiovascular Research Berlin

Registry information

Important dates

Study start
2008
Primary completion
2017
Study completion
2017
First posted
Mar 15, 2018
Registry last updated
Mar 15, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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